Individual Biochemical Behaviour Versus Biological Robustness: Spotlight on the Regulation of Cytochrome c Oxidase

Abstract

During evolution from prokaryotes to eukaryotes, the main function of cytochrome c oxidase (COX), i.e., the coupling of oxygen reduction to proton translocation without the production of ROS (reactive oxygen species) remained unchanged demonstrating its robustness. A new regulation of respiration by the ATP/ADP ratio was introduced in eukaryotes based on nucleotide interaction with the added COX subunit IV. This allosteric ATP-inhibition was proposed to keep the mitochondrial membrane potential (ΔΨ(m)) at low healthy values and thus prevents the formation of ROS at complexes I and III. ROS have been implicated in various degenerative diseases. The allosteric ATP-inhibition of COX is reversibly switched on and off by phosphorylation of COX at a serine or threonine. In more than 100 individual preparations of rat heart and liver mitochondria, prepared under identical conditions, the extent of allosteric ATP-inhibition varied. This variability correlates with the variable inhibition of uncoupled respiration in intact isolated mitochondria by ATP. It is concluded that in higher organisms the allosteric ATP-inhibition is continually switched on and off by neuronal signalling in order to change oxidative phosphorylation from optimal efficiency with lower rate of ATP synthesis under resting conditions (low ΔΨ(m) and ROS production) to maximal rate of ATP synthesis under active (working, stress) conditions (elevated ΔΨ(m) and ROS production).

The brown and brite adipocyte marker Cox7a1 is not required for non-shivering thermogenesis in mice

“…With increased uncoupling protein 1 (Ucp1) expression and activation during cold exposure, COX-activity increases to compensate for an increased proton leak 10 11 . This can principally be achieved either by an increase in mitochondrial abundance per cell, an increased abundance of assembled COX holoenzyme per mitochondrial mass, or by modifications of enzyme activity by phosphorylation 45 or by an exchange of subunit isoforms. The latter is a COX-unique property with regard to respiratory chain complexes 46 as can be demonstrated by deletion of single, organ-specific isozymes.…”

A High Precision Method for Quantitative Measurements of Reactive Oxygen Species in Frozen Biopsies

“…Also, before recommending dietary antioxidants measuring oxidative stress can be useful [30]. However, production of ROS is highly individual and depends on the external and internal stress of the organism [31]–[33]. This means that it is hard to control the amount of internal ROS and antioxidant production in the organism, or the stress added by anaesthesia and the surgery.…”

The subunit composition and function of mammalian cytochrome c oxidase

“…The reader is referred to several recent publications for a detailed discussion of this topic (Covian and Balaban, 2012;Helling et al, 2012b;Hüttemann et al, 2012b;Ramzan et al, 2012). We here only briefly discuss a small number of phosphorylation sites for which a function has been suggested.…”